Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:4.6.1.2 (guanylate cyclase)
8,497 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tolerance to the cyclic GMP-mediated vasodilator action of nitroglycerin develops with prolonged exposure and may be mediated either by formation of less nitric oxide from nitroglycerin or by desensitization of soluble guanylate cyclase to activation with nitric oxide. In the latter case, smooth muscle cells tolerant to nitroglycerin should show cross-tolerance to nitric oxide released from sydnonimines and endothelial cells (endothelium-derived relaxing factor). Therefore cultured smooth muscle cells from rabbit aorta were pretreated for 1 h with vehicle or high concentrations (0.55 mM) of nitroglycerin or the sydnonimine SIN-1. The formation of cyclic GMP induced by subsequent small doses of nitroglycerin, sydnonimine SIN-1 and endothelium-derived relaxing factor (released from cultured endothelial cells) was compared with the changes in activation of soluble guanylate cyclase, cyclic GMP formation and vasodilation in response to the same stimuli in similarly pretreated segments from rabbit thoracic aortae. Both cultured and native smooth muscle cells remained responsive to stimulation with sydnonimine SIN-1 and endothelium-derived relaxing factor after pretreatment with nitroglycerin, vehicle, or sydnonimine SIN-1, even though they were tolerant to nitroglycerin after pretreatment with nitroglycerin. In contrast, activation of soluble guanylate cyclase by nitroglycerin and sydnonimine SIN-1 was attenuated in homogenates of nitrate-tolerant aortae. The findings suggest that nitroglycerin tolerance in intact cells does not involve desensitization of soluble guanylate cyclase, because in intact cells nitrate tolerance can be overcome by direct activators of soluble guanylate cyclase.
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PMID:Endothelium- and sydnonimine-induced responses of native and cultured aortic smooth muscle cells are not impaired by nitroglycerin tolerance. 257 Mar 62

It is now generally accepted that organic nitrates generate their vasodilator action via production of nitric oxide. However, the cellular location of the metabolic enzyme(s) responsible for such conversion has not been defined. We examined the production of nitric oxide, via chemiluminescence detection, by various cellular fractions of the bovine coronary artery. We were able to show that the highest activity resides in the plasma membrane. Future isolation and characterization of such metabolic systems will greatly assist our understanding of nitrate action and tolerance. Several cellular mechanisms for nitrate tolerance have been proposed. Among the most popular theories is the "intracellular sulfhydryl depletion hypothesis" originally proposed by Needleman et al. The primary supportive data for this mechanism are that exogeneously added thiols (such as N-acetylcysteine) can potentiate the in vivo activity of nitroglycerin and can partially reverse nitrate tolerance. We showed that a cellular-impermeant thiol, viz: glutathione, can also potentiate the hemodynamic effect of nitroglycerin in rats. We subsequently showed that exogenously administered thiols can promote the formation of vasoactive S-nitrosothiols in blood. Thus, the beneficial effects of thiols on nitrate action might be mediated through an extracellular pathway. Another cellular mechanism for nitrate tolerance suggested that tolerance is caused by an alteration of the enzyme, guanylate cyclase. We showed, however, that blood vessels made tolerant to nitroglycerin remain fully responsive (in terms of in vitro relaxation) toward nitric oxide and S-nitrosothiols. These data showed that, as far as relaxation is concerned, nitrate tolerance did not cause a significant alteration of guanylate cyclase activity toward nitric oxide and S-nitrosothiols.
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PMID:Cellular mechanisms of nitrate action. 257 80

Previous studies have demonstrated that the D-enantiomer of isoidide dinitrate (IIDN) is 10-fold more potent than the L-enantiomer for relaxation and cyclic GMP accumulation in isolated rat aorta. To test whether preferential biotransformation of D-IIDN to a species that activates guanylate cyclase is the basis for this observed enantioselectivity, paired segments of rat aorta were exposed to D- and L-IIDN and the tissue accumulation of the parent compound and the formation of their respective metabolites (D- and L-isoidide mononitrate, IIMN) were determined. The extent of relaxation of rat aorta following exposure to 2 microM D-IIDN was greater than that by L-IIDN over a 5-minute time course, and this was associated with a higher rate of D-IIDN biotransformation to D-IIMN at all time points. In addition, the rate of D-IIDN biotransformation was greater than that of L-IIDN at most IIDN concentrations tested. By contrast, the amount of D- and L-IIDN in the tissue was the same at all time points and concentrations tested, indicating that selective uptake of D-IIDN into blood vessels did not occur. When tissues were made tolerant to organic nitrate-induced relaxation by treatment with a high concentration of glyceryl trinitrate, the biotransformation of both D- and L-IIDN was attenuated. This suggests that mechanism-based biotransformation may be affected during tolerance development. Furthermore, the association of preferential D-IIDN biotransformation with its greater potency for vasodilation and cyclic GMP accumulation suggests than an enantioselective site for biotransformation is an important component of organic nitrate-induced vasodilation.
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PMID:Differential biotransformation of the enantiomers of isoidide dinitrate in isolated rat aorta. 262 80

Vascular smooth muscle relaxation in response to chemically diverse naturally occurring neurotransmitters and autacoids has been attributed to the formation and/or release of one or more vascular endothelium-derived relaxing factors (EDRFs) distinct from prostacyclin. The chemical, biochemical, and pharmacological properties of one such EDRF resemble closely the properties of nitric oxide (NO). Thus, both arterial and venous EDRFs as well as authentic NO cause heme-dependent activation of soluble guanylate cyclase, endothelium-independent vascular and nonvascular smooth muscle relaxation accompanied by tissue cyclic GMP formation, and inhibition of platelet aggregation and adhesion to endothelial cell surfaces. EDRF from artery, vein, and freshly harvested and cultured aortic endothelial cells was recently identified as NO or a labile nitroso species as assessed by chemical assay and bioassay. Endothelium-derived NO (EDNO) has an ultrashort half-life of 3-5 s due to spontaneous oxidation to nitrite and nitrate, both of which have only weak biological activity. EDNO can be synthesized from L-arginine and possibly other basic amino acids and polypeptides, perhaps by oxidative metabolic pathways that could involve polyunsaturated fatty acid-derived oxygen radicals. Inorganic nitrite could serve as both a stored precursor and an inactivation product of EDNO. EDNO and related EDRFs may serve physiological and/or pathophysiological roles in the regulation of local blood flow and platelet function.
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PMID:Endothelium-derived nitric oxide: actions and properties. 264 68

Tolerance develops during the prolonged use of organic nitrates in patients with chronic heart failure in a fashion similar to its development in patients with angina pectoris, the magnitude of tolerance development being directly proportional to the frequency of dosing. When nitroglycerin is given continuously or when isosorbide dinitrate is administered frequently throughout the day (e.g., every 4h), haemodynamic tolerance develops completely in most patients within 24-48h. Such tolerance can be avoided, however, when these drugs are given intermittently (e.g., every 8 or 12 h). Unfortunately, most clinical trials with isosorbide dinitrate have attempted to produce continuous haemodynamic effects by administering the drug at frequent intervals; this may explain why these trials have produced equivocal results. Two mechanisms have been proposed to explain the development of tolerance in patients with chronic heart failure. According to the first hypothesis, tolerance develops as a result of the depletion of intracellular sulfhydryl groups that are essential to the ability of nitroglycerin to activate guanylate cyclase--the key enzyme in the action of nitrates on blood vessels. According to the second hypothesis, tolerance develops as a result of the activation of endogenous neurohormonal systems; the resulting vasoconstriction limits the direct effects of the nitrovasodilators. A better understanding of both mechanisms may lead to interventions that will circumvent the development of tolerance and enhance the efficacy of long-term nitrate therapy.
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PMID:The clinical significance of nitrate tolerance in patients with chronic heart failure. 266 3

Since there is evidence suggesting that nicorandil (SG-75) relaxes coronary arterial smooth muscle by increasing cGMP levels, the effects of this vasodilator on soluble guanylate cyclase from bovine coronary arteries were studied more closely. It was found that nicorandil stimulated guanylate cyclase dose-dependently (3-30 mM) up to 100-fold the control value. Similar to nitroglycerin but in contrast to sodium nitroprusside, cysteine (0.5-20 mM) was required to obtain this stimulation. All other investigated thiols, except thiosalicylic acid which was partially able to mimic the cysteine effect, were ineffective. As evident from time course studies, nicorandil induced stimulation of guanylate cyclase was characterized by a lag-phase which could be avoided by preincubating the enzyme with nicorandil. The stimulatory effect of nicorandil was diminished in the presence of methylene blue, ferricyanide or hydroquinone. These results give further evidence that a) nicorandil exerts its vasodilating effect via stimulation of guanylate cyclase and b) nitrate esters, such as nitroglycerin or nicorandil, stimulate the enzyme, at least in vitro, only in the presence of cysteine or, to a lesser extent, thiosalicylic acid.
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PMID:Stimulation of coronary guanylate cyclase by nicorandil (SG-75) as a mechanism of its vasodilating action. 285 1

According to our present understanding organic nitrates like glycerine trinitrate mediate their pharmacological effect by an intracellular stimulation of the enzyme guanylate cyclase (E.C. 4.6.1.2.) [1, 10]. The exact molecular mechanism underlying the process of enzyme activation is still a matter of controversial discussion. But there is general agreement in literature about the fact that organic nitrate compounds are able to activate the enzyme guanylate cyclase only in the presence or by the interaction of the amino acid cysteine [3, 5]. The stimulatory activity of nitric oxide-containing compounds may be due, at least in part, to the formation of active, unstable intermediate S-nitrosothiols, i.e. S-nitrosocysteine in case of the organic nitrates [7]. According to Craven and DeRubertis [2], the active intermediates of guanylate cyclase stimulation are represented by nitric oxide-heme complexes. There is, however, substantial evidence that the organic nitrates have to be cleaved before they become biologically active. During the transformation which takes place in the presence of cysteine or by means of enzymatic catalysis, nitric oxide radicals are reductively split off the molecule from which (via the intermediate formation of salpetric acid) the nitric oxide is liberated as the essential stimulatory agent. In this study we examined the transformation of glycerine trinitrate and other organic nitrates under the influence of different thiols and a purified soluble rat liver guanylate cyclase preparation. At the same time the stimulation of guanylate cyclase in the presence of the thiols mentioned was quantitatively estimated. Only in case of cysteine did we find a strict correlation between the liberation of nitric oxide from different organic nitrates and the degree of enzyme activation. Several other thiols were also able to liberate nitric oxide, but surprisingly enough, there was no equivalent stimulation of guanylate cyclase.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Evidence for a correlation between nitric oxide formation by cleavage of organic nitrates and activation of guanylate cyclase. 286 57

Guanylate cyclase in high speed supernatant fractions obtained from rat thoracic aorta or human coronary arteries pretreated with nitroglycerin exhibited a marked desensitization to activation by nitroglycerin, nitroprusside, and nitric oxide. However, activation of soluble guanylate cyclase by arachidonic acid was unaffected by pretreatment of vessels with nitroglycerin. Furthermore, activation of soluble guanylate cyclase by protoporphyrin IX was increased 4-fold when vessels were pretreated with nitroglycerin. Soluble guanylate cyclase partially purified from nitroglycerin-pretreated rat thoracic aorta by immunoprecipitation with a specific monoclonal antibody exhibited persistent desensitization to nitrate-induced activation. These data suggest that nitroglycerin-induced desensitization of guanylate cyclase to activation by nitrovasodilators represents a stable alteration of the enzyme. In contrast, activation by protoporphyrin IX of guanylate cyclase immunoprecipitated from nitroglycerin-pretreated or control vessels was not significantly different. This suggests that the mechanism of protoporphyrin activation of guanylate cyclase is different than the mechanism with nitrovasodilators. Activation of particulate guanylate cyclase by Lubrol-PX, hemin, or atrial natriuretic factor was not significantly different with enzyme prepared from nitroglycerin-pretreated or control vessels from rat and human. Thus, nitroglycerin-induced desensitization of rat thoracic aorta or human coronary artery results in a relatively stable molecular alteration of soluble guanylate cyclase such that the enzyme is specifically less sensitive to activation by nitrovasodilators whereas the effects of other activators of the enzyme are either unchanged or increased.
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PMID:Desensitization to nitroglycerin in vascular smooth muscle from rat and human. 287 10

Organic nitrates produce their pharmacological effect by an intracellular stimulation of the enzyme guanylate cyclase (E. C. 4.6.1.2). We could show that the stimulatory effect of organic nitrates on the activity of guanylate cyclase is strongly dependent on the number of nitrate residues per molecule. The EC50 values found for the tetra-, tri- di-, and mononitrates differed from each other by the factor 4. In contrast to investigations carried out with the perfused isolated Langendorff heart there was no correlation between the lipophilicity of these substances and the EC50 in our guanylate cyclase preparation, as penetration of cell membranes is not required. Other authors have found that organic nitrates are able to activate the enzyme guanylate cyclase only in the presence of cysteine. There is general agreement in the literature that organic nitrates have to be cleaved before they become biologically active. During the transformation which takes place in the presence of cysteine or by means of enzymatic catalysis the nitric oxide radical is liberated as the essential stimulatory agent. We found a strict correlation between the liberation of nitric oxide from different organic nitrates (GTN, IMDN, IIDN, ISDN, IS-2-N, IS-5-N) and the degree of enzyme activation. The Ec50 values of the organic nitrates were calculated from the concentration response curves which were obtained with a guanylate cyclase preparation from rat liver in the presence of cysteine. The degradation of the organic nitrates was measured under the same conditions by means of HPLC. The amount of nitric oxide set free was calculated by using the velocity constants k of organic nitrate degradation.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Thiol-dependent activation of guanylate cyclase by organic nitrates]. 287 91

We examined the effect of nitroglycerin (GTN) tolerance on an important determinant of nitrate-antianginal action, large coronary artery dilation, in 11 chronically instrumented conscious dogs. In addition, endothelium-mediated coronary artery dilation was studied because this shares a common dilator pathway with the nitrates, i.e., activation of soluble guanylate cyclase. With long-term GTN (1.5 micrograms/kg/min iv for 5 days) the diameters of the left circumflex and anterior descending coronary arteries showed an initial increase of 8.2 +/- 0.3% and 10.8 +/- 0.9%, respectively, returning to control levels by the second to third day of treatment. On days 4 and 5, the dose-response relations for GTN-induced epicardial artery dilation were shifted (p less than .01) to 17- to 20-fold higher doses. However, there was no attenuation of epicardial artery dilation induced by SIN-1 (n = 7), another activator of guanylate cyclase, or of endothelium-mediated dilation assessed both as flow-dependent dilation (n = 7) and as direct intra-arterial acetylcholine-induced dilation (n = 4). In addition, there was no clear tolerance to the peripheral vascular actions of GTN responsible for reflex tachycardia and increased coronary flow. We conclude that a moderate degree of nitrate tolerance to epicardial artery dilation does not affect the responsiveness to other exogenous or endogenous activators of guanylate cyclase. However, this tolerance to epicardial artery dilation, together with the maintenance of peripheral vascular actions that can induce reflex tachycardia, result in a potentially unfavorable balance of GTN effects.
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PMID:Long-term nitroglycerin treatment: effect on direct and endothelium-mediated large coronary artery dilation in conscious dogs. 288 35


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